Metabolism, disease and drug design

Drug discovery and the changing landscape of biology

By Clifton Berry & John Kozarich

The ultimate goal of most scientists who work in biological chemistry is to understand and affect human health. As our understanding of biological processes at both the macroscopic and molecular levels increases in complexity, new approaches and concepts rapidly feed into drug discovery programs, producing new tools that further inform our understanding in an iterative way. Drug discovery is an early adopter of biochemical innovation, and this 2016 American Society for Biochemistry and Molecular Biology annual meeting symposium will highlight some of the approaches being taken to engage the most recent advances in biochemistry and molecular biology.

Big data: adding -omics

The front line of contemporary omics is moving beyond transcripts and proteins to the more analytically demanding tasks of quantifying lipids and metabolites. The first session will highlight these advances and their integration with the blueprints (DNA and RNA) and effectors (protein). It also will consider how activity-based probes applied in cell or tissue lysates have accelerated our understanding of the proteome in normal and disease states.

Mechanism matters

The second session will consider how biochemical insights into processes as basic as protein synthesis provide new guide posts for innovative approaches to treating disease. Pathway-driven genetic methods of understanding druggability can take a lot of the guesswork out of target selection. And bringing together a detailed understanding of the enzymology and mechanism of neurodegenerative diseases rapidly is advancing therapeutic approaches using the tools of structure-based design.

Natural beauty: harnessing evolution

Natural products are fascinating examples of evolutionary masterpieces, often perfectly fit for their natural niche. The third session will discuss how chemically modifying these works of natural art often is daunting, but new metagenomic approaches to identifying families of naturally occurring analogs have the potential to transform the field. Integrating natural products with structural biology and detailed mechanistic understanding provides new hope for exploiting naturally evolved antibacterials against humankind’s most ancient diseases.

A thousand words

The final session will dig into how modern imaging methodologies accelerate understanding of complex systems, diseased or normal. Imaging mass spectrometry now allows unparalleled understanding of small molecule distribution and spatial localization in tissues. Activity-based imaging promises to transform pathogen detection. Whole-body imaging using positron emission tomography, or PET, and computed tomography, or CT, routinely is used clinically, but new generations of probes built on understanding the biochemistry of disease are potentially transformative.